ANNEXIN A2 AND ITS ASSOCIATED SIGNALING PATHWAYS THAT PROMOTE PANCREATIC CANCER METASTASES
Rucki, Agnieszka Anna
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Pancreatic ductal adenocarcinoma (PDA) is still one of the deadliest cancers worldwide, mostly because it is highly resistant to chemotherapy and radiation. Most patients are diagnosed at late stages of the disease when metastases occurred resulting in the poor PDA outcomes. Despite new therapies developed for other cancers, very little progression has been made in the field of therapeutics for PDA; making understanding and targeting PDA of upmost importance. The hallmarks of PDA are the presence of dense desmoplastic reaction and high prevalence of perineural (PNI) and lymphatic (LVI) invasion. The stroma co-develops with the neoplasm and plays a role in the regulation/progression of PDA. PNI and LVI are thought to represent the initial steps of metastasis. PNI is also believed to be a mechanism for cancer-related pain, one of the most debilitating symptoms in pancreatic cancer patients. Here, we showed that Annexin A2 (AnxA2) is essential for PDA metastasis formation in a transgenic mouse model. In addition, we demonstrated that heterogeneously distributed stromal signals regulate the pro-metastatic function of AnxA2 at tyrosine 23 and 333 and that dual signaling inhibition of the signaling pathways (Hh/IGF-1/IGF-1R and HGF/c-Met) suppresses PDA metastasis. Moreover, we elucidated the pathway downstream of AnxA2, and showed that AnxA2 regulates the secretion of Sema3D and regulates its binding to PlxnD1 on PDA cells that act in both autocrine and paracrine fashion to facilitate PNI and PDA metastases. We also provided preclinical evidence of sensitization of primary tumors to conventional chemotherapy by inhibition of those pro-metastatic stromal signals. And lastly, we demonstrated that Sema3D expression in human PDA is associated with poor survival, metastases and PNI making it a suitable biomarker for prediction of PDA patient outcome. This thesis, with the application of in vitro and in vivo PDA models, provides new evidence for a previously unknown mechanism of metastases and PNI in PDA that can be translated into the development of targeted therapies for pain and metastasis management for PDA patients.